Abstract Memory CD8+ T cells are essential adaptive effector cells of immune defenses because they are extremely efficient at sensing intracellular pathogens and tumors. The chief effector feature of CD8+ T cells is their ability to recognize and kill infected and ?abnormal? cells but they also produce multiple effector cytokines and chemokines that contribute to orchestrate protective immune responses. The cellular and molecular stepwise mechanisms by which memory CD8+ T cells in vaccinated hosts are reactivated and mediate protection is not well understood. Answering to this question has the potential to lead to novel strategies to harness or redirect the power of CD8+ T cells to the benefit of the host in many therapeutic contexts. Over the years, using mice immunized with the intracellular bacterium Listeria monocytogenes (Lm) as model, we have contributed to show that during recall infection, vaccine-induced memory CD8+ T cells quickly sense sets of inflammatory cytokines released from various antigen-presenting cells (APCs), which initiate a rapid effector program in the memory CD8+ T cells. This includes notably the secretion of the potent immunomodulatory cytokine IFN? which further signals and activates microbicidal functions inside phagocytes, a necessary process for efficient protection of vaccinated hosts. Yet, IFN? is secreted to similar extent whether cognate T cell antigens are present or not. Protection, however, is antigen-specific, suggesting that other factors distinct from memory CD8+ T cell-derived IFN? account for IFN?-mediated protection. This proposal investigates these factors and their regulation in the memory CD8+ T cells, which APCs provide cognate antigen to the memory CD8+ T cells during recall infection and the dynamic interactions of memory CD8+ T cells and killer phagocytes using cutting-edge intravital imaging approaches. Finally, we will also dissect the mechanisms of IFN?-dependent cell-autonomous defenses that are triggered inside activated phagocytes. We predict successful completion of the proposed work will have a broad impact in the field of T cell biology and vaccines, and potentially important therapeutic implications.